Hofmann, S. R., Carlsson, E., Kapplusch, F., Carvalho, A. L., Liloglou, T., Schulze, F., Abraham, S., Northey, S., Russ, S., Surace, A. E. A., Yoshida, N., Tsokos, G. C., & Hedrich, C. M. (2021). Cyclic AMP Response Element Modulator-alpha Suppresses PD-1 Expression and Promotes Effector CD4(+) T Cells in Psoriasis. J Immunol, 207, 55-64.
Abstract
Effector CD4(+) T lymphocytes contribute to inflammation and tissue damage in psoriasis, but the underlying molecular mechanisms remain poorly understood. The transcription factor CREMalpha controls effector T cell function in people with systemic autoimmune diseases. The inhibitory surface coreceptor PD-1 plays a key role in the control of effector T cell function and its therapeutic inhibition in patients with cancer can cause psoriasis. In this study, we show that CD4(+) T cells from patients with psoriasis and psoriatic arthritis exhibit increased production of IL-17 but decreased expression of IL-2 and PD-1. In genetically modified mice and Jurkat T cells CREMalpha expression was linked to low PD-1 levels. We demonstrate that CREMalpha is recruited to the proximal promoter of PDCD1 in which it trans-represses gene expression and corecruits DNMT3a-mediating DNA methylation. As keratinocytes limit inflammation by PD-1 ligand expression and, in this study, reported reduced expression of PD-1 on CD4(+) T cells is linked to low IL-2 and high IL-17A production, our studies reveal a molecular pathway in T cells from people with psoriasis that can deserve clinical exploitation.
Last updated on 02/17/2024